tbuckley/cabot-search huggingface dataset:
EPCO-27. RECONSTRUCTION OF THE SPATIAL ECOSYSTEM OF GLIOBLASTOMA REVEALS RECURRENT RELATIONSHIPS BETWEEN TUMOR CELL STATES AND TUMOR MICROENVIRONMENT
Authors: Bruno Adabbo, Simona Migliozzi, Luciano Garofano, Young Taek Oh, Sakir H Gultekin, Fulvio D'Angelo, Evan R Roberts, Daniel C Bilbao, Pedro M Davila, Sion L Williams, Benjamin B Currall, Michele Ceccarelli, Anna Lasorella, Antonio Iavarone
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor, with no curative treatment options. Multiple studies have characterized at single cell resolution the GBM as being composed of transcriptional cell states interconnected with components in the tumor immune microenvironment (TME). Our group proposed and validated the first single cell guided functional classification of GBM in four tumor-intrinsic cell states which informed clinical outcome and delivered therapeutic options. However, single cell technologies lack the spatial relationships among the cell states of GBM and between GBM cell states and TME. Spatially resolved transcriptomic technologies are emerging as powerful tools to reconstruct the spatial architecture of a tissue. We performed spatial transcriptomics of multicellular regions of interest (ROI) in 8 IDH wild-type GBM with both CosMx Spatial Molecular Imager, which analyzes 1,000 RNA probes and 64 proteins at single cell resolution, and GeoMx Digital Spatial Profiler which profiles the whole transcriptome (~18,000 genes) at ROI resolution. We integrated the two platforms to define single cell states and non-malignant cells and developed a computational deconvolution approach for CosMx spatial data which utilized GeoMx ROI resolved transcriptomic profiles as a-priori information to predict cell type abundances. Spatial deconvolution of CosMx derived single cells revealed spatial segregation of the tumor cell clones and cellular states and highlighted recurrent patterns of cell states, distinct TME cell types associated with coherent histopathological features across multiple samples. Our studies established a scalable approach to resolve the transcriptional heterogeneity of GBM and reconstruct the architecture of GBM cell states and tumor microenvironment.
PATH-11. POOLED <i>IN VIVO</i> ASSAY TO CHARACTERIZE GLIOBLASTOMA INVASION AT THE SINGLE-CELL RESOLUTION
Authors: Toshiro Hara, Rony Chanoch-Myers, Lillian Bussema, Alissa Greenwald, Jinan Behnan, Hiroaki Wakimoto, Rossella Galli, Itay Tirosh, Mario Suva
Journal: Neuro-Oncology (2023)

Abstract Tumor cell invasion is the main characteristic of glioblastoma and one of the obstacles to successful treatments. Nonetheless, molecular features of invading glioblastoma cells remain elusive and poorly characterized, such as their gene expression states and microenvironmental influences. Recently, we described cell state heterogeneity in glioblastoma by single-cell RNA-sequencing (scRNA-seq) and uncovered the contribution of immune cells to the heterogeneity. However, it is unclear whether the cell states observed in clinical specimens are implicated in invading glioblastoma cells in the surgically inaccessible brain parenchyma. It is also unclear whether the cell states are correlated to the non-immune microenvironment. As a tool for probing these questions, we developed an in vivo approach with mixtures of human glioblastoma spheroid lines for mouse intracranial xenografts. We validated this with 20 patient-derived models and identified, by scRNA-seq, in vivo models capable of infiltrating along the periphery of either neurons or blood vessels. We profiled and characterized programs, states, and clonality of invading glioblastoma cells by comparing cells from the contralateral invasive edge to their counterparts at the original bulk tumor. This comparative analysis showed evidence of a bi-directional transitioning model for cells residing in different spatial niches. Importantly, presence of an OPC-like state was significantly associated with invasion phenotype regardless of the infiltration routes. Our results suggest that cellular plasticity may be a prerequisite for the invasive phenotypes, urging further assessment to identify critical regulators of the cell states. In conclusion, this work describes pooled in vivo assays for the rapid interrogation of patient-derived xenografts, coupling the gene expression phenotypes with cellular functions such as invasion.
NIMG-51. RADIOGRAPHIC IMPROVEMENT IN A PATIENT WITH OLIGODENDROGLIOMA UNDERGOING TREATMENT FOR ACUTE MYELOID LEUKEMIA
Authors: Mauricio Perez Davila, Lourdes Mendez, Joachim Baehring
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: The standard chemotherapy for treating oligodendroglioma consists of a combination of procarbazine, lomustine, and vincristine (PCV). The combination of hypomethylating agents, like azacitidine, and BCL2 inhibitors like venetoclax have not been formally studied in the treatment of glial tumors. The combination of these two drugs is commonly used to treat acute myeloid leukemia, with IDH mutant disease being a particularly sensitive subtype. CASE REPORT: A 48-year-old man was diagnosed with a left frontal, grade II oligodendroglioma following multiple episodes of speech arrest and right-hand numbness. He was subsequently treated with six cycles of PCV with a minor response. After slow progression over eight years, the tumor started displaying contrast enhancement. While planning for radiation therapy, he presented to the Emergency Department with severe fatigue and shortness of breath. Workup led to a diagnosis of pure erythroid leukemia, with molecular and cytogenetic studies suggesting a neoplasm related to prior exposure to cytotoxic chemotherapy. He was treated with three cycles of venetoclax and azacitidine, but unfortunately, the erythroleukemia progressed after a transient response to this treatment. On the other hand, however, a re-staging MRI brain showed a remarkable reduction of his tumor size of approximately 40% per RANO criteria. The patient was off steroids and remained neurologically asymptomatic during this time. Discussion: The use of azacitidine for the treatment of IDH mutant gliomas has been reported in the literature, with mixed results that might suggest at least some benefit in a subtype of patients. Other studies have also suggested that the BCL2 gene is associated with treatment resistance and tumor recurrence in gliomas. Our case presents an interesting observation that combining a hypomethylating agent with a BCL2 inhibitor might convey clinical and radiographic benefits for patients with relapsed IDH mutant gliomas.
PATH-01. COMPARATIVE EVALUATION OF THE DIAGNOSTIC AND PROGNOSTIC PERFORMANCE OF CNSIDE™ VERSUS STANDARD CYTOLOGY FOR LEPTOMENINGEAL DISEASE
Authors: Haley Appel, Muni Rubens, Anshul Saxena, Mukesh Roy, Alexander Mohler, Rupesh Kotecha, Matthew Hall, Manmeet Ahluwalia, Minesh Mehta, Serguei Castaneda, Yazmin Odia
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE We compared the real-world performance of the cerebrospinal fluid (CSF) CNSide™ versus cytology assays in diagnosing leptomeningeal disease (LMD). METHODS Consecutive patients with suspected LMD from January 2020 to December 2022 who underwent lumbar punctures for CSF cytology and CNSide™ analyses were reviewed. LMD diagnosis was defined by EANO criteria. We used descriptive statistics, confusion matrix, Kaplan Meier curves, and Cox proportional regression methods to analyze outcomes. RESULTS 87 patients with median age of 63 years (range:23-93) were evaluated, of which 82 (94%) met EANO positive (possible, probable, or confirmed criteria) cohort. Of the EANO cohort, 33 (40%) had uncontrolled systemic disease and 25 (46%) were on systemic therapy with medium/high CNS penetrance. The median time from initial cancer diagnosis to LMD was 31 months (range:21-43). LMD was diagnosed by CSF cytology (EANO confirmed) in 23 cases, all identified by CNSide™. CNSide™ identified an additional 13 cases, increasing diagnostic yield by 56.5%. Commonest primary histologies in the EANO cohort were breast (36, 44.0%) and lung (34, 41.5%); 18 (53.0%) of lung cancers harbored actionable molecular alterations, while breast cancers expressed hormone receptors in 27 (75%) and HER2 alterations in 8 (22%). Median overall survival (OS) for the CNSide™ cohort was 19.5 weeks (95%CI:11.0-28.0) and 31 weeks (95%CI:21-43) for EANO positive cases. Median OS for breast patients in CNSide™ cohort was 42 (R: 15-65) weeks, about 7-fold that of lung (median 6.5, R: 2-20). There was no correlation between OS and cell density by CNSide™ (HR:1.000, 95%CI:0.999-1.001, p=0.909). OS was higher for cases treated with intrathecal chemotherapy (HR:0.189, 95%CI:0.053-0.672, p=0.010), but not statistically different by radiotherapy modality (HR, 0.583, 95%CI:0.264-1.287, p=0.181). CONCLUSIONS This retrospective, single-institution, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant, cell-based molecular CSF analyses.
TMIC-23. UNRAVELLING THE HETEROGENEITY OF GLIOBLASTOMA'S VASCULAR LANDSCAPE
Authors: Zoe Woolf, Susan Li, Molly Swanson, Clinton Turner, Patrick Schweder, Jason Correia, Richard Faull, Thomas Park, Michael Dragunow
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma tumours are highly vascular and angiogenic. However, they are also heterogeneous, comprising many different macro- and microenvironments. Reflecting this, tumour-associated blood vessels are variable in their distribution, structure, and function. Despite the significance of vasculature in the development and progression of glioblastoma, its complexity remains poorly defined. Therefore, characterising vascular diversity across the glioblastoma landscape is a crucial step in the development of targeted therapies. METHODS 40 glioblastoma and 5 epilepsy cases were immunohistochemically labelled with a vascular antibody panel (PDGFRβ, ColIV, αSMA, UEA-1 and GFAP) to identify and subtype vessels. Single-vessel image analysis was performed to analyse vascular coverage and to classify vascular subtypes based on marker co-expression. Labelling with haemoglobin, ZO-1, and claudin-5 allowed for the evaluation of vascular leakage and blood-brain barrier integrity. Tissue segmentation was performed to analyse vascular coverage, vascular subtypes, and vascular integrity across the tumour macro-environment. RESULTS No significant difference in gross vascular coverage was found between tumour and epilepsy tissue. However, vascular coverage within glioblastoma varied significantly depending on the tumour macro-environment. Whilst vascular coverage in the tumour periphery was comparable to epilepsy tissue, increased vessel density was observed in the intermediate tumour zone, followed by decreased vessel density towards the tumour core. Reflecting this variation, multiple vessel subtypes, including previously described glomerular microvascular proliferation, mother vessels, vascular malformations and hyperplastic vessels, were identified. These tumour vessels display highly irregular shapes, sizes, and cellular compositions. Finally, glioblastoma tissue displayed a significant increase in haemoglobin leakage and a decrease in vascular integrity compared to epilepsy tissue. CONCLUSION Characterising this vascular landscape provides valuable insights for treatment strategies related to hypoxia and angiogenesis, two key factors driving tumour growth. Indeed, targeting specific vessel subtypes to address compromised vascular function and aberrant vascularisation may improve outcomes for glioblastoma patients.
STEM-21. DETERMINATION OF RACIAL DISPARITIES IN GLIOMA THROUGH RAP1B/NOTCH -INDUCED TUMORIGENESIS AND STEMNESS
Authors: Shanchun Guo, Alyssa Guo, Jason Li, Vanajothi Rama, Hannah Akpobiyeri, Breanna Hudson, Mingli Liu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The incidence of GBM and survival rates after diagnosis vary significantly by race, with Caucasian Americans (CAs) having higher incidence and lower survival rates than African Americans (AAs). Accumulating evidence suggests that the failure of current therapies is partly attributed to the presence of glioma stem cells (GSC), leading to tumor progression and recurrence. Our recent work demonstrates that Ras-associated protein 1 (Rap1), a Ras-like small GTP-binding protein superfamily member, has roles in glioma cell proliferation and invasion. METHODS 1) The TCGA database was analyzed to investigate the predictive role of Rap1b in glioma patients. 2) The immunohistochemical staining for Rap1b1 was performed using the rabbit polyclonal anti-Rap1b in glioma tissue microarrays (TMA) from 76 glioma patients with 10 normal individuals. The staining intensity of cells in TMA was evaluated in three different bright fields (≥100 cells/field). The semi-quantitative HSCORE was calculated for Rap1b. 3) The mechanism of the oncogenic role of Rap1b in glioma was examined using in vitro cell culture. RESULTS 1. TCGA data showed that Rap1b mRNA is highly expressed in GBM patients compared to normal controls, indicating that Rap1b is a potential oncotarget in GBM. Expression of Rap1b is associated with worse survival in glioma patients, especially in CAs, but not in AAs. 2. The TMA data showed that elevated Rap1b protein expression correlates with grades in glioma patients. 3. In vitro studies showed that GSCs exhibit high levels of Rap1b, silencing Rap1b decreases glioma cell growth and invasion through G1/S arrest and the induction of apoptosis, as well as reduces Notch1 signaling in glioma cells; while potentiates GBM cell response to TMZ. CONCLUSION This study provided new knowledge of Rap1b’s potential as a therapeutic drug target for GBM therapy and revealed biological diversity across races and unaddressed health disparities.
EXTH-71. AUTOMATED AND MULTIPLEXED COMBINATORIAL DRUG SCREENING OF FDA-APPROVED DRUGS IDENTIFIES POTENTIAL SYNERGISTIC DRUG PARTNERS FOR THE TREATMENT OF AGGRESSIVE MENINGIOMAS
Authors: Gerhard Jungwirth, Viktor Braun, Rolf Warta, Amir Abdollahi, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2023)

Abstract The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or by overcoming resistance to single drugs. In search of effective synergistic drug combinations for the treatment of aggressive meningiomas, we performed an automated and multiplexed combinatorial drug screening of 166 FDA-approved anticancer drugs in three grade 3 meningioma cell lines. Three anaplastic meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response matrices (1 to 1000 nmol/L) for 48 hours by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. To demultiplex cell viability from a single well, fluorescence as a surrogate marker for viability was measured before adding an ATP-based end-point viability assay, which served as an independent combined result of all cell lines (combined group). Synergism was calculated by the ZIP Synergy model and was defined as a ZIP score over 10. This drug screening effort generated 13695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in the combined group (n = 188, 1.37%), followed by IOMM-Lee (n = 157, 1.14%), and KT21-MG1 (n = 122, 0.88%). The lowest number of synergistic combinations was observed in NCH93 (n = 75, 0.54%). Interestingly, 86 combinations were uniquely found in IOMM-Lee, 54 in KT21-MG1, and 20 in NCH93, indicating specific tumor vulnerabilities. 19 drug combinations were observed in all cell lines. Of those, the drugs Temsirolimus, Gemcitabine, and Romidepsin were highly enriched. For example, mTORi Temsirolimus concordantly showed strong synergism with the androgen receptor antagonist Darolutamide in all cell lines (ZIP score: 27.75, P&amp;lt; .0001). This comprehensive combinatorial drug screening identified synergistic drug-drug partners for the treatment of aggressive meningiomas. Validation studies in patient-derived meningioma organoids are ongoing.
CTNI-02. A LONGITUDINAL THERAPY RESPONSE MONITORING STUDY IN SUBJECTS WITH LEPTOMENINGEAL METASTASES USING CNSIDE COMPARED TO STANDARD OF CARE (CSF CYTOLOGY, CLINICAL EVALUATION, IMAGING)
Authors: Seema Nagpal, Michael Youssef, Sue Beruti, Laura Gillis, Kelly Gordon, Barbara Blouw, Priya Kumthekar
Journal: Neuro-Oncology (2023)

Abstract LM is diagnosed via clinical evaluation, neuroaxis neuroimaging (MRI brain and spine), and CSF cytology. These methods have limited sensitivity and specificity, and lack the ability to quantitatively measure the LM’s response to treatment. These hindrances create challenges in LM diagnosis and management for physicians. CNSide is a commercially available Laboratory Developed Test (LDT) that is analytically validated for the detection and characterization of tumor cells in the CSF, and run commercially in Biocept’s CLIA-certified, CAP-accredited laboratory. Physicians order CNSide testing at their discretion for patients that have a suspicion of LM. To evaluate the performance of CNSide for LM disease management in a controlled setting, Biocept is conducting a prospective, multi-center clinical study (FORESEE, NCT05414123) involving patients previously diagnosed with NSCLC or Breast Cancer and a suspicion or diagnosis of LM per standard of care (SOC) management, including clinical assessment, radiographic evaluation, and CSF cytology. At baseline and at designated time points throughout treatment, matched CSF samples will be analyzed in parallel with standard of care CSF cytology and CNSide at Biocept along with time matched neuroimaging and clinical evaluation. The primary end point of the trial is the proportion of decision points during LM treatment in which physicians indicated that CNSide aided in their decision making. Physicians will also indicate which component of the test aided in management, modeling other similar studies that measure the effect of serum biomarker results on clinical management of cancer. Secondary end points include diagnostic comparison to clinical evaluation, cytology, and radiographic results, and determining the sensitivity, specificity, PPV and NPV of CNSide in the detection of CSF tumor cells (cytology being the reference standard).
CTNI-01. LONG-TERM RESULTS FROM A PHASE 1 TRIAL OF SPINE SBRT IN INOPERABLE PATIENTS WITH CORD COMPRESSION
Authors: Amol Ghia, Nandita Guha-Thakurta, Jing Li, Mary Frances McAleer, Tina Briere, Claudio Tatsui, Paul Brown, Thomas Beckham, Chenyang Wang, D Nana Yeboa, Eric Chang, Laurence Rhines
Journal: Neuro-Oncology (2023)

Abstract PURPOSE/OBJECTIVE We seek to establish the feasibility of using spine stereotactic radiosurgery (SSRS) allowing for spinal cord dose constraint relaxation as the primary management of metastatic epidural spinal cord compression (MESCC) in inoperable patients monitoring for radiation myelopathy (RM) and radiographic local control (LC). MATERIAL/METHODS Patients with radiation naïve MESCC were enrolled on this prospective Phase 1 trial. Single fraction SSRS was delivered to a dose of 18 or 24 Gy. Spinal cord constraint relaxation was performed in sequential cohorts from an initial allowable Dmax cohort of 10 Gy up to 16 Gy only if tumor progression occurred without RM. RESULTS Thirty two patients enrolled on the trial of which 4, 12, 8 and 8 were in the 10 Gy, 12 Gy, 14 Gy and 16 Gy cord Dmax cohorts, respectively. At baseline, there were 10 sites with MESCC Grade 1B, 10 sites with Grade 1C, 9 sites with Grade 2, 2 sites with Grade 1A, and 1 site with Grade 3 disease. Of the 28 evaluable patients, the median overall survival was 32.3 months (range 5.8-122.6 mo). The 1-year and 5-year LC was 84.5% and 79.5%. The 2-year LC did not statistically differ between the 14-16 Gy cord Dmax combined cohorts and the 10-12 Gy cord Dmax combined cohorts (92.9% vs. 62.9%, p = 0.15). With a median clinical follow-up of 22.7 months (range 3-122.3 mo), there were no cases of RM including in the 13 patients who survived at least 3 years. In the cohort receiving a cord Dmax of 16 Gy, there were no cases of RM with a median follow-up of 18.6 mo (range 9.0-97.1 mo). CONCLUSION With long-term follow-up, these data demonstrate that SSRS is a safe and effective tool in patients with MESCC. Cord constraint relaxation may be considered in inoperable patients with MESCC.
QLTI-09. INTEGRATION OF NEURO-ONCOLOGY CLINICAL PATHWAYS IN PROVIDENCE SOUTHERN CALIFORNIA CLINICAL RESEARCH NETWORK: UPDATED INFO AFTER 17 MONTHS OF UTILIZATION
Authors: Thomas Bott, Nanor Parseghian, Trisha Babcock, Akanksha Sharma, Naveed Wagle, Jose Carrillo, Tiffany Juarez, Santosh Kesari
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION ClinicalPath is an evidence-based oncology decision support and analytics tool for cancer care. ClinicalPath’s treatment recommendations are prioritized based on efficacy, toxicity, and cost, by a nationwide committee of oncologists. The pathways are updated quarterly with the most recent evidenced-based treatment options that healthcare providers choose for adoption to help standardize therapy, improve quality, and decrease cost. The pathway system also allows for local clinical trial mapping to promote clinical trial awareness and help increase enrollment. ClinicalPath provides clinical pathways delivering personalized, evidence-based oncology guidance at the point of care. ClinicalPath’s network in North America serves more than 2,000 cancer physicians, within 54 practices in 31 states (15 academic medical centers, 29 hospital systems, and 9 community practices). Population: Our population is derived from multiple hospitals in Southern California within the Providence Health System. Methodology: Medical oncologists and Advanced Practice Providers received training on ClinicalPath before go-live. ClinicalPath was integrated into the Epic EHR in multiple Southern CA hospitals in a single month in Jan 2022. RESULTS On reviewing the utilization data within our Southern California region from Jan 2022-May 2023, 2681 treatment decisions were made across all cancers, with 86.7% of cancer patients treated on pathway. Of these decisions, 114 were made within the neuro-oncology specialty, and 70.2% of those cancer patients were treated on pathway. CONCLUSION We successfully integrated and initiated ClinicalPath in a multiple hospital-affiliated community oncology clinical trial network which included a strong neuro-oncology presence. We are actively working across our Southern California Region to map locally available clinical trials to promote awareness and increase enrollment. Provider utilization and patient on-pathway rates are actively monitored and will be updated.